polymers Review Chitosan and its Derivatives for Ocular Delivery Formulations: Recent Advances and Developments Alexandra Zamboulis *, Stavroula Nanaki, Georgia Michailidou, Ioanna Koumentakou, Maria Lazaridou, Nina Maria Ainali, Eleftheria Xanthopoulou and Dimitrios N. Bikiaris * Laboratory of Polymer Chemistry & Technology, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; sgnanaki@chem.auth.gr (S.N.); michailidougeorgia18@gmail.com (G.M.); iwanna.koumentakou@gmail.com (I.K.); marlazach@chem.auth.gr (M.L.); ainali.nina@gmail.com (N.M.A.); elefthxanthopoulou@gmail.com (E.X.) * Correspondence: azampouli@chem.auth.gr (A.Z.); dbic@chem.auth.gr (D.N.B.) Received: 8 June 2020; Accepted: 3 July 2020; Published: 8 July 2020   Abstract: Chitosan (CS) is a hemi-synthetic cationic linear polysaccharide produced by the deacetylation of chitin. CS is non-toxic, highly biocompatible, and biodegradable, and it has a low immunogenicity. Additionally, CS has inherent antibacterial properties and a mucoadhesive character and can disrupt epithelial tight junctions, thus acting as a permeability enhancer. As such, CS and its derivatives are well-suited for the challenging field of ocular drug delivery. In the present review article, we will discuss the properties of CS that contribute to its successful application in ocular delivery before reviewing the latest advances in the use of CS for the development of novel ophthalmic delivery systems. Colloidal nanocarriers (nanoparticles, micelles, liposomes) will be presented, followed by CS gels and lenses and ocular inserts. Finally, instances of CS coatings, aiming at conferring mucoadhesiveness to other matrixes, will be presented. Keywords: chitosan; derivatives; ocular drug delivery; ophthalmic applications; mucoadhesion; antibacterial; nanoparticles; hydrogels; coatings 1. Introduction Ocular diseases affect a growing number of people across the globe. Some pathological ophthalmic conditions, such as glaucoma, diabetic retinopathy, or age-related macular degeneration, cause severe visual impairment that can ultimately lead to blindness. In spite of their relative accessibility, or rather because of it, eyes are well-protected organs and successful ocular drug delivery is one of the important challenges the pharmaceutical industry has to face. Ocular tissues are protected from foreign substances by a series of static and dynamic barriers and protective mechanisms, as illustrated in Figure 1 [1]. Tear turnover, reflex blinking, and nasolacrimal drainage drain agents away from the eye surface. The corneal epithelium and conjunctiva cover and protect the ocular surface. Additionally, the blood–ocular barriers (blood–aqueous and blood–retina) limit the access of compounds from systemic circulation. This defensive system is further assisted by enzymes and other barriers (corneal stroma, sclera, etc.). Eye drops are the most frequently prescribed form of ocular treatment [3]. This is due to several inherent advantages of topical instillation of eye drops such as their non-invasive character and easy administration, resulting in high patient compliance and their immediate action. Despite their convenience, it is generally accepted that due to the ocular barriers, only 5% of the administered drug actually reaches its target, as shown in Figure 2 [4–8]. Moreover, only a small volume (approximately 30 μL) of eye drop formulation can be instilled in the eye. As a result, concentrated solutions have to be administered, and frequent instillations are necessary to reach a therapeutic result [2,9–11]. Polymers 2020, 12, 1519; doi:10.3390/polym12071519 www.mdpi.com/journal/polymers